1. health and fitness
2. therapy

0021-972X/98/$03.00/0
Journal of Clinical Endocrinology and Metabolism
Copyright © 1998 by The Endocrine Society
Vol. 83, No. 2
Printed in U.S.A.
Growth Hormone Deficiency in Adulthood and the
Effects of Growth Hormone Replacement: A Review
PAUL V. CARROLL, EMANUEL R. CHRIST AND THE MEMBERS OF GROWTH HORMONE
RESEARCH SOCIETY SCIENTIFIC COMMITTEE: B. Å. BENGTSSON, L. CARLSSON,
J. S. CHRISTIANSEN, D. CLEMMONS, R. HINTZ, K. HO, Z. LARON,
¨ NKSEN, T. TANAKA, AND M. THORNER
P. SIZONENKO, P. H. SO
I. Introduction
II. Body Composition
A. Body composition in adults with GH-deficiency
compared with healthy controls
1. Lean body mass
2. Fat mass
3. Fluid volume
B. Effect of GH replacement
1. Lean body mass
2. Fat mass
3. Fluid volume
III. Bone Mineral Density and Bone Metabolism
A. Epidemiological data
B. Bone mineral denisity and bone metabolism in adults
with GH deficiency compared with healthy controls
C. Effects of GH replacement on bone mineral density
and bone metabolism in adults with GH deficiency
IV. Muscle Strength
V. Exercise Performance
VI. Cardiovascular System
VII. Metabolism
A. Energy expenditure
B. Protein metabolism
C. Carbohydrate metabolism
D. Lipid and lipoprotein metabolism
1. The plasma lipid and lipoprotein profile in
adults with GH deficiency
2. Effect of GH replacement on the plasma lipid and
lipoprotein profile in adults with GH deficiency
3. Proposed mechanism of action of GH on lipid
and lipoprotein metabolism
VIII. Skin
IX. Immune Function
X. Psychological Well-Being and Quality of Life
XI. Reported Adverse Effects of GH replacement
XII. Concluding Remarks
and in a large series, pituitary adenoma was the commonest
cause of adult hypopituitarism (2). The incidence of adultonset (AO) GH deficiency is not known, but indirect estimates based on the incidence of pituitary tumors suggest an
incidence of 10 people/million annually. In contrast, childhood-onset (CO) GH deficiency is most commonly idiopathic
and is not necessarily associated with other pituitary hormone deficiencies.
The limited supplies of pituitary-derived GH restricted
research into the use of GH in adults and limited knowledge
of the role of GH after the cessation of linear growth. An early
study, in which a 35-yr-old hypopituitary adult reported
increased vigor, ambition, and well-being after GH replacement, suggested that GH may have biological actions in
adulthood (3). More recent evidence suggests that adults
with hypopituitarism have reduced life expectancy (2, 4),
possibly related to GH deficiency (5). The availability of
recombinant GH has led to intensive investigation of the
effects of GH in health and disease, and over the past decade,
numerous studies have focused on the effects of GH replacement in the adult with GH deficiency.
The first placebo-controlled trials of GH replacement in the
GH-deficient adult were reported in 1989 (6, 7). These and
subsequent investigations have led to the recognition of a
specific clinical syndrome in adults with long standing GH
deficiency. This syndrome is associated with characteristic
symptoms, signs, and investigative findings. The main features are listed in Table 1. Many studies have assessed the
effects of GH replacement on these symptoms and signs. The
majority of these data has resulted from both formal randomized placebo-controlled trials and smaller open studies.
Consistently, these studies have demonstrated that adults
with GH deficiency are both physically and psychologically
less healthy than their age-matched peers, and that GH replacement results in substantial and sustained benefits. This
review details the important features resulting from GH deficiency and summarizes the information, available up to the
beginning of 1997, relating to the effects of GH replacement.
I. Introduction
G
H DEFICIENCY in the human adult most commonly
results from pituitary or peripituitary tumors and
their treatment (1). The majority of these tumors are benign,
II. Body Composition
In vitro and in vivo studies have shown that GH is anabolic,
lipolytic, and has an antinatriuretic action (8 –10). Each of
these properties has an impact on body composition. Most of
the studies investigating body composition have referred to
a two-compartment model consisting of fat mass and lean
body mass (LBM).
Received July 25, 1997. Accepted October 15, 1997.
Address all correspondence and requests for reprints to: GRS Secretariat, Medical Department M, Aarhus Kommunehospital, DK-8000,
Aarhus C, Denmark.
382
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INVITED REPORT OF A WORKSHOP
TABLE 1. The clinical features of GH deficiency in adults
Background
Need for GH treatment as a child
Known pituitary pathology 6 previous treatment
Full conventional pituitary hormone replacement
Symptoms
Abnormal body composition
Reduced lean body mass
Increased abdominal adiposity
Reduced strength and exercise capacity
Impaired psychological well-being
Reduced vitality and energy
Depressed mood
Emotional lability
Impaired self-control
Anxiety
Increased social isolation
Signs
Overweight with predominantly central (abdominal) adiposity
Thin, dry skin; cool peripheries; poor venous access
Reduced muscle strength
Reduction exercise performance
Depressed affect, labile emotions
Investigations
Stimulated GH level below 3 mg/L
Low or low-normal serum IGF-I
Elevated serum lipids, particularly LDL cholesterol
Reduced lean body/increased fat mass
Reduced bone mineral density
A wide range of techniques has been used to assess body
composition and have been reviewed by de Boer et al. (11).
They all rely on assumptions derived from healthy subjects,
e.g. constant hydration state of lean body, constant intracellular potassium concentration, or a constant fat-free extracellular compartment. These assumptions may not be valid
in AO GH deficiency. Nevertheless, despite the methodological differences, the findings from these studies are strikingly
similar. In addition, recent studies using computerized tomography (CT) (12) and magnetic resonance imaging (MRI)
(13) have confirmed the previous findings.
A. Body composition in adults with GH deficiency compared
with that in healthy controls
1. Lean Body Mass (LBM). Reduced LBM is an important
feature of AO GH deficiency. Initial studies demonstrated a
mean reduction in LBM of 7– 8%, corresponding to approximately 4 kg lean tissue (6). Subsequent studies have confirmed these results (12, 14 –16).
2. Fat mass. Salomon et al. (6) were the first to demonstrate
that fat mass was higher by a mean of 7% in GH-deficient
patients compared with predicted values based on age, sex,
and height. Using a wide range of measurement techniques,
this figure has been confirmed by other investigators (15,
17–22).
The fat mass distribution has been assessed in a number
of studies by waist/hip ratio, skin fold thickness (6, 17, 21),
CT scan (12), and MRI (13) with consistent results. The excess
fat accumulates in a central (abdominal) distribution, mostly
in the visceral component. In epidemiological studies, this
abdominal distribution has been associated with an increased risk of mortality and morbidity from cardiovascular
disease.
383
3. Fluid volume. Studies employing a radioisotope dilution
technique and bioimpedance measurements indicate that total body water is reduced in AO GH deficiency (20, 21). This
is mainly due to a reduction in extracellular water (ECW) (15,
23, 24). Recent studies suggest that reduced plasma volume
(PV) (24) and total blood volume (25) contribute to the reduced ECW.
B. Effect of GH replacement
The studies investigating the effect of GH on body composition are summarized in Table 2. The range of the GH
dose used in these trials was 0.1– 0.5 IU/kgzweek (5–25
mg/kgzday).
1. Lean Body Mass. In all reported studies, LBM has been
shown to increase by a mean of 2–5.5 kg with GH replacement treatment (6, 7, 12–17, 21, 26 –32). This has been equally
observed in patients with AO and CO GH deficiency (33).
Skeletal muscle, the most prominent component of LBM, has
been demonstrated to increase in a parallel manner. GH
treatment results in significant increases in thigh muscle
cross-sectional area (14, 28).
2. Fat mass. GH replacement therapy has resulted in a mean
reduction in fat mass of approximately 4 – 6 kg in GH-deficient adults (6, 7, 12–17, 21, 26 –32). A recent study suggests
that this reduction occurs similarly in both CO and AO GH
deficiency (33). Anthropometric measurements indicate that
the most important change occurs in the abdominal region
(6). In addition, studies using CT (12) and MRI (13) have
shown that the reduction in abdominal fat mass is mainly
due to a reduction in visceral fat mass.
3. Fluid volume. In studies using radionuclide dilution methods and bioimpedance analysis, GH therapy resulted in an
increase in total body water (12, 33–35), particularly in ECW
within 3–5 days (22, 24, 26, 36). A short term study failed to
demonstrate an increase in PV after 2 weeks of GH treatment
(36), but a longer study has shown that an increase in PV
occurs after at least 3 weeks of GH replacement therapy (24).
In a recent study, GH therapy resulted in an 400-mL increase
in total blood volume after 3 months of treatment (35).
The well known antinatriuretic effect of GH appears to
involve a direct action of GH and/or insulin-like growth
factor I (IGF-I) on renal tubular sodium reabsorption,
but there is also evidence for an activation of the reninangiotensin system (24, 36).
III. Bone Mineral Density (BMD) and Bone
Metabolism
A. Epidemiological data
A radiological study of 36 adults with long standing GH
deficiency demonstrated that 17% had reduced vertebral
height, consistent with vertebral fracture, and a further 19%
had features of osteopenia (37). In a retrospective study (38),
the fracture rate in 89 adult patients with GH deficiency was
significantly higher (24.1% vs. 11.8%) than that in a control
population (n 5 390). These data suggest that adults with GH
deficiency are at increased risk of osteoporotic fractures.
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TABLE 2. The effect of GH replacement therapy on body composition in adult GH deficiency
Yr
n
Salomon (6)
Jorgensen (7)
Orme (27)
Binnerts (15)
Whitehead (14)
Amato (21)
Bengtsson (12)
Chong (16)
Herlitz (34)
Jorgensen (28)
Hansen (31)
Beshyah (29)
Author
1989
1989
1992
1992
1992
1993
1993
1994
1994
1994
1995
1995
24 (MO)
21 (CO)
8 (AO)
8 (AO)
14 (MO)
7 (CO)
10 (AO)
7 (AO)
16 (MO)
10 (CO)
29 (AO)
38 (MO)
De Boer (22)
Snel (13, 17)
Lonn (30)
1995
1995
1996
Moller (24)
1996
Johannsson (26) 1996
Johannsson (165) 1996
Baum (32)
Hoffman (36)
Christ (35)
Attanasio (33)
1996
1996
1997
1997
Design
DBPC
DBPC/Co
Open
Open
DBPC/Co
Open
DBPC/Co
Open/controlled
Open
Open
DBPC
DBPC
Open
46 (CO) DBPC
30 (MO) Open/controlled
9 (AO) DBPC/Co
Open
7 (AO) Open/controlled
34 (AO) Open
68 (AO) DBPC
Open
32 (AO) DBPC
7 (AO) DBPC/Co
13 (MO) DBPC
74 (CO) DBPC
99 (AO) Open
Duration (months)
Method
LBM
FM
6
4
2
6
6/6
6
6/6
3
6
36
12
6
12/18
12
6
6
24
1
24
6
12/18
18
7 days
3
6
12/18
AP, TBK, BIA
CT, AP
AP, TBK, BIA, DEXA, CT
BIA, DL
DEXA, CT
BIA
TBK, BIA, DL, CT
DL
DL
CT
DEXA
AP, TBK, DL
AP, TBK, DL
BIA
AP, DEXA, MRI
CT
a
a
a
a
a
a
a
a
s
s
s
s
s
s
s
s
a
a
a
a
s
s
s
s
a
a
s
s
a
a
a
a
a
s
s
s
s
BIA, DL
TBK, DL, TBN, BIA
DEXA
DEXA
DEXA
BIA, DL
BIA, DL
AP, BIA
AP, BIA
TBW
ECW TBV/PV RCM
a
a
a
a
s
a
a
s
a
a/a s/s a/a
a
a
a
a
a
N
a
a
n, Number of patients; LBM, lean body mass; FM, fat mass; TBW, total body water; ECW, extracellular water; TBV, total blood volume; PV,
plasma volume; RCM, red cell mass; DBPC, double blind placebo-controlled; Co, cross-over; TBK, total body potassium; BIA, bioimpedance; CT,
computerized tomography; AP, anthropometry (skin fold thickness, waist/hip ratio); DEXA, dual energy x-ray absorptiometry; DL, isotope
dilution; TBN, total body nitrogen; MRI, magnetic resonance imaging; CO, childhood-onset GH deficiency; AO, adult-onset GH deficiency; MO,
mixed onset GH deficiency; a/s, statistically significant increase/decrease vs. baseline; N, no change from baseline.
TABLE 3. Bone mineral density in adults with GH deficiency compared with healthy age-matched subjects
Author
Yr
n
Method
Kaufman (40)
Johansson (43)
Hyer (41)
Amato (21)
O’Halloran (39)
Bing-You (44)
Thoren (47)
De Boer (42)
Holmes (45)
Beshyah (19)
Rosen (46)
Degerblad (48)
1992
1992
1992
1993
1993
1993
1993
1994
1994
1995
1995
1995
30M (CO)
29 (AO)
60 (CO)
7 (CO)
12 (CO)
14 (AO)
33 (MO)
70M (CO)
26 (AO)
64 (MO)
95 (MO)
88 (MO)
SPA, DEXA
DEXA
DEXA
DPA
SPA, QCT
DEXA
DEXA
DEXA
SPA, QCT, DEXA
DEXA
DPA
DEXA
Localization
Total BMD
FA-p
FA-d
L2–L4
s
s
s
s
s
s
s
s
s
s
s
s
s
s
s
s
s
s
s
s
s
s
s
s
sa
sb
FN
Ward
N
s
s
s
s
s
N
s
sb
n, Number of patients; M, male patients only; FA-p, forearm proximal (cortical bone); FA-d, forearm distal (trabecular and cortical bone);
L2–L4, lumbar spine; FN, femoral neck; Ward, Ward’s triangle; DEXA, dual energy x-ray absorptiometry (L2–L4, FN, Ward); SPA, single photo
absorptiometry (FA-p. FA-d); DPA, double photo absorptiometry (L2–L4); QCT, single energy quantitative computed tomography (trabecular
bone mineral density L2–L4); CO, childhood-onset GH deficiency; AO, adult-onset GH deficiency; MO, mixed onset GH deficiency.
a
Only in patients less than 55 yr of age.
b
Only in female patients.
B. BMD and bone metabolism in adults with GH deficiency
compared with those in healthy controls
The studies investigating BMD in AO GH deficiency are
summarized in Table 3. Using different techniques these
studies have universally demonstrated reduced bone mass at
different skeletal sites in patients with CO (21, 39, 40 – 42), AO
(43, 44, 45), and mixed onset (19, 46 – 48) GH deficiency compared with that in healthy control subjects.
Studies investigating bone formation (osteocalcin) and resorption markers (urinary pyridinolines) have yielded con-
flicting results. Osteocalcin levels have been shown to be
higher (41), lower (49), or equal (50) in patients with AO GH
deficiency compared with those in normal controls. In addition, markers of bone resorption have been shown to be
increased in patients with multiple pituitary deficiencies, but
not in patients with isolated GH deficiency (51, 52).
Bone histology of patients with mainly CO GH deficiency
showed high trabecular bone volume, increased bone erosion, increased osteoid thickness, and increased mineralization lag time, indicating a delayed bone mineralization (53).
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INVITED REPORT OF A WORKSHOP
C. Effects of GH replacement on BMD and bone metabolism
in adults with GH deficiency
The studies investigating the effects of GH on BMD at
different skeletal sites are summarized in Table 4. The dose
of GH used in these trials was 0.25 IU/kgzweek (12.5 mg/
kgzday), except in the study by Amato et al. (21), in which a
dose of 0.1 IU/kgzweek (5 mg/kgzday) was used. Baum et al.
(32) administered a starting dose of 0.2 IU/kgzweek (10 mg/
kgzday) and adjusted the dose to maintain normal IGF-I
levels.
GH replacement has not been shown to increase bone mass
in the short term (3– 6 months) (14, 15, 21, 47, 48, 54 –58); in
several studies reduced BMD has been recorded after 6 or 12
months of GH therapy (47, 48, 58, 59), but after more than 12
months treatment increases of 4 –10% above baseline have
been demonstrated (32, 39, 54, 55, 60 – 62). An open study of
the effects of GH replacement in 44 patients with AO GH
deficiency demonstrated an increase in BMD after 2 yr of GH
treatment (62). In this study there was an associated increase
in bone remodeling that was sustained over 24 months. The
gain in BMD was most marked in those patients with low
BMD before commencement of GH therapy.
The studies investigating the effect of GH on bone metabolism are summarized in Table 5. Serum bone formation
(osteocalcin, bone alkaline phophatase, bone Gla protein,
and carboxyl-terminal propeptide of type I procollagen) and
urinary resorption markers (deoxypyridinoline, pyridinoline, and cross-linked telopetide of type I collagen) increased
in both short and long term studies, indicating an activation
of bone remodeling (15, 32, 48, 50, 52, 54, 55, 57, 58, 62).
Interestingly, in patients with AO GH deficiency, bone formation appears to be increased at 6 months, with no further
change throughout treatment (32, 33). In contrast, patients
385
with CO GH deficiency showed a steep increase up to 12
months of GH therapy, followed by a sharp decrease to
baseline value after 18 months GH therapy (33). 1,25-Hydroxyvitamin D increased in one study (15) and was unchanged after 12 months in another (58). PTH did not change
(15, 56) or decreased (12, 47, 48, 58), whereas 25-hydroxyvitamin D remained unchanged (58). In three studies (12, 56,
58), serum phosphate and calcium levels were reported to
increase after 6 –12 months of treatment.
Histomorphometry of transiliac bone biopsies of 36 patients with AO GH deficiency after 6 –12 months of GH
treatment showed an increase in cortical thickness, increased
bone formation, and decreased bone resorption. Trabecular
bone volume remained unchanged (63).
In summary, AO GH deficiency is associated with reduced
bone mass, as assessed by BMD measurements. The available
data provide evidence that GH is an osteo-anabolic hormone
when given to GH-deficient adults. The findings in most of
the trials suggest that GH has a biphasic effect; after an initial
predominance of bone resorption, stimulation of bone formation leads to a net gain in bone mass after 12–24 months
of treatment. Whether these changes in bone metabolism will
result in less osteopenia and a reduced fracture rate in adults
with GH deficiency requires long term study.
IV. Muscle Strength
The alterations in body composition that occur in GH
deficiency with reduced LBM result in a mild to moderate
reduction in muscle strength. Isometric quadriceps force has
been shown to be reduced in GH-deficient adults compared
with that in matched normal controls (64), and this finding
has been supported by a more recent study (65). The reduction in cross-sectional muscle area may account for this find-
TABLE 4. Effects of GH replacement on bone mineral density in adults with GH deficiency
Author
Yr
n
Design
Duration (months)
Whitehead (14)
Binnerts (15)
O’Halloran (39)
Amato (21)
Thoren (47)
Vandeweghe (54)
1992
1992
1993
1993
1993
1993
14 (MO)
8 (AO)
12 (CO)
7 (CO)
20 (MO)
15 M, (CO)
Beshyah (56)
Beshyah (57)
Degerblad (48)
1994
1995
1995
38 (MO)
38 (MO)
68 (MO)
Holmes (59)
1995
20 (AO)
Kann (55)
1995
13 (MO)
Rosen (61)
Johannsson (62)
Baum (32)
Hansen (58)
Ter Maaten (60)
1996
1996
1996
1996
1996
34
44
32
29
36
DBPC/Co
Open
DBPC
Open
DBPC
DBPC
Open
DBPC
Open
DBPC
Open
DBPC
Open
DBPC
Open
Open
Open
DBPC
DBPC
Open
6/6
6
12
6
6
6
12/18
6
12/18
6
12
6
12
6
12/24
36
24
18
12
48
(AO)
(AO)
(AO)
(AO)
M (?)
Method
Localization
Total BMD
QCT
SPA, DPA
SPA, QCT
SPA
DEXA
SPA, DPA
DEXA
DEXA
DEXA
DEXA
SPA, QCT, DEXA
SPA, DPA
SPA, DPA
DEXA
DEXA
DEXA
DEXA
DEXA
FA-p
N
a
N
N
N/N
s
s
a
a
s
a
FA-d
N
a
N
N
N/a
s
N
N
N/N
s
N
N
N/a
a
s
s
L2–L4
FN
Ward
N
a
N
N
N/a
N
N/N
N
N
s
s
a
N/a
a
a
a
N
a
s
N
N
s
N
a
a
a
N
a
a
a
N
a
n, Number of patients; M, male patients; DBPC, double blind placebo-controlled study design; Co, cross-over study; FA-p, forearm proximal
(cortical bone); FA-d, forearm distal (trabecular and cortical bone); L2–L4, lumbar spine; FN, femoral neck; Ward, Ward’s triangle; DEXA, dual
energy x-ray absorptiometry (L2–L4, FN, Ward); SPA, single photo absorptiometry (FA-p. FA-d); DPA, double photo absorptiometry (L2–L4);
QCT, single energy quantitative computed tomography (trabecular bone mineral density L2–L4); a/s, statistically significant increase/
decrease vs. baseline; N, no statistically significant change from baseline; CO, childhood-onset GH deficiency; AO, adult-onset GH deficiency;
MO, mixed onset GH deficiency.
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TABLE 5. The effects of GH replacement on bone metabolism in adults with GH deficiency
Author
Yr
n
Design
Duration
BF
BR
Johansen (50)
Whitehead (14)
Binnerts (15)
Sartorio (52)
Bengtsson (12)
Vandeweghe (54)
1990
1992
1992
1993
1993
1993
21 (MO)
14 (MO)
8 (AO)
8 (CO)
10 (AO)
15 M, (CO)
a
20
38
38
10
Degerblad (48)
1995
68 (MO)
Holmes (59)
Hansen (58)
Johannsson (62)
Baum (32)
Attanasio (33)
1995
1996
1996
1996
1997
20
29
44
32
20
41
a
a
a
a
a/N
a
a
a/a
a
a/a
a
a
a
a
a
a
CO a AO a
CO a/N, AO a/a
a
a
1993
1994
1995
1995
4/4
6/6
6
6
6/6
6
12/18
6
6
12/18
6
12/24
6
12
6
12
24
12
6
12/18
a
Thoren (47)
Beshyah (56)
Beshyah (57)
Kann (55)
DBPC/Co
DBPC/Co
Open
Open
DBPC/Co
DBPC
Open
DBPC
DBPC
Open
DBPC
Open
DBPC
Open
DBPC
DBPC
Open
DBPC
DBCO
Open
(MO)
(MO)
(MO)
(MO)
(AO)
(AO)
(AO)
(AO)
(CO)
(AO)
a
a/N
N
a
a
a/a
a
a
a
a
a
PTH
25OHD
1,25-(OH)2D
aP
N
N
a
a
a
N
s
a
s
N
N
a
a/a
a
s
N
N
a
a
n, Number of patients; M, male patients only; DBPC, double blind placebo-controlled study design; Co, cross-over study; BF, bone formation
markers (osteocalcin, serum bone Gla protein, PIIINP, bone alkaline phosphatase); BR, bone resorption markers (hydroxyproline, deoxypyridinoline, ICTP); 25OHD and 1,25-(OH)2D, active vitamin D metabolites; aP, alkaline phosphatase; CO, childhood-onset GH deficiency; AO,
adult-onset GH deficiency; MO, mixed onset GH deficiency; a/s, statistically significant increase/decrease vs. baseline; N, no statistically
significant change.
ing, but even allowing for this, weakness is evident. Lack of
conditioning and endurance training may be responsible for
the shortfall.
Several studies have addressed the effects of GH replacement on muscle strength (7, 14, 41, 65, 66). In these studies,
limb-girdle force was increased after 6 months of GH treatment (66), but neither isometric quadriceps force (7, 14, 65,
66) nor quadriceps torque (67) increased significantly in any
of the studies. This occurred despite clear increases in thigh
muscle cross-sectional area. Only after more prolonged GH
treatment (at least 12 months) was a significant increase in
quadriceps force demonstrated (65, 68), with a further increase and normalization seen after 3 yr (28).
V. Exercise Performance
Cuneo et al. (64, 66, 69) were the first to study exercise
performance and capacity in adults with GH deficiency. The
patients had increased shoulder fatigability and reduced
quadriceps force, even allowing for the reduction in muscle
mass (64). Maximal exercise performance in GH-deficient
adults has been assessed in several studies using cycle ergometry (7, 14, 27, 69). Before treatment, values for maximum
oxygen uptake were significantly reduced, being, on the
average, 72– 82% of those predicted for age, sex, and height
(14, 69).
After GH treatment (0.25– 0.50 IU/kgzweek; 12.5–25 mg/
kgzday) for up to 6 months, maximum oxygen uptake increased significantly (7, 14, 64), virtually reaching predicted
values (69). Similar findings were reported by Nass et al. (70)
from a double blind, placebo-controlled study of 20 adults
with GH deficiency. In this study, 6 months of GH replacement resulted in significant improvements in exercise capacity and maximum oxygen uptake. When isolated muscle
groups were tested, GH therapy increased hip flexor (66) and
knee extensor (68) strength. Exercise performance is deter-
mined both by muscle mass and cardiac performance (71).
Cuneo et al. corrected exercise capacity for changes in LBM
and found no alteration from baseline (69), suggesting that
the increased exercise performance is mainly caused by the
GH-associated increased muscle mass. An increase in erythrocyte mass/oxygen transport capacity due to a stimulatory
effect of IGF-I on erythropoiesis may also contribute to an
increased exercise capacity (25, 72–74). The effects of GH
replacement on the cardiovascular system are dealt with
below.
VI. Cardiovascular System
Epidemiological data suggest that adults with hypopituitarism have reduced life expectancy compared with that of
healthy controls, with a greater than 2-fold increase in mortality from cardiovascular disease (2, 4). These findings were
confirmed and extended by Erfurth et al. (75), who found a
standardized mortality ratio (SMR) of 1.74 for cardiovascular
disease among 344 patients with hypopituitarism in the
south of Sweden compared with that in the healthy population in the same catchment area. The increased risk of death
was mostly attributable to cerebrovascular disease (SMR 5
3.39), especially among female patients (SMR 5 4.91). Similar
mortality rates have been demonstrated from a study in the
UK; however, the cardiovascular mortality was less evident
than in earlier studies (4). GH deficiency has been proposed
as the variable accounting for this increased mortality (5).
These data support the hypothesis that long standing GH
deficiency in adulthood predisposes to the development of
premature atherosclerosis.
Rosen et al. (76) compared known cardiovascular risk factors in 104 adults with GH deficiency with healthy controls
from a population study. The patients had a higher body
mass index, higher plasma triglycerides (TG), and lower high
density lipoprotein cholesterol (HDL-C). In addition, there
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was a higher incidence of hypertension in the GH-deficient
subjects compared with controls. The mechanisms responsible for the increased cardiovascular mortality remain
largely unknown, but carotid artery ultrasonography has
demonstrated increased intima-medial thickening and intimal plaque formation (77) and reduced arterial compliance
(78) in hypopituitary adults. Johannson et al. (79) compared
levels of plasminogen activator inhibitor-1, fibrinogen, blood
lipids, and blood pressure in 20 adults with GH deficiency
with those in healthy subjects. The patients had increased
TG, plasminogen activator inhibitor-1 activity, and fibrinogen compared with controls. These changes may contribute
to increased artherogenic propensity and cardiovascular
disease.
The role of GH in the regulation of cardiac function and
structure has not yet been fully defined. A comprehensive
case report demonstrated cardiac chamber dilatation, reduced ventricular wall thickness, and decreased myocardial
fibrillar content in a patient with a 20-yr history of GH deficiency (80). GH therapy for 3 months was associated with
a decrease in ventricular diameter and increases in wall
thickness, ejection fraction, and myofibrillar content. A similar clinical response to GH replacement has been reported
in a patient with advanced heart failure (81).
Cuneo et al. (82) reported a small, but significant, increase
in resting left ventricular end-diastolic volume and stroke
volume after GH treatment, which were attributed to an
increase in plasma volume (preload) secondary to the antinatriuretic effect of GH. There was also an increase in left
ventricular mass, which occurred in the absence of any
change in mean arterial pressure (afterload). The mean increase in left ventricular mass of 5% was comparable with the
5–10% increase in thigh muscle and lean body mass in the
same patients, suggesting an anabolic action of GH on not
only skeletal but also cardiac muscle. In contrast, a subsequent placebo-controlled study of 20 adults with GH deficiency failed to demonstrate any alteration in cardiac structure after 6 months GH replacement (70).
Two studies comparing echocardiographic findings have
demonstrated reduced left ventricular mass and impaired
systolic function in adults with GH deficiency compared
with healthy controls (21, 83). Treatment with GH for 6
months normalized these indexes, and 6 months after cessation of therapy, cardiac function had returned to baseline.
Six months of GH replacement have been shown to increase
left ventricular mass (18%), stroke volume (28%), and cardiac
output (43%) and reduce peripheral vascular resistance (84)
in GH-deficient adults. A sustained effect on cardiac performance has been reported in two open studies up to 3 yr after
commencement of GH therapy (85, 86).
Cuocolo et al. (87) studied cardiac function in 14 adults
with GH deficiency and 12 matched controls using radionuclide scanning. The GH-deficient patients were studied
before and after GH replacement. Compared with controls,
the patients had decreased left ventricular ejection fraction,
decreased stroke volume index, and decreased cardiac index.
GH therapy for 6 months increased these variables, reversing
these deficits in cardiac function. In contrast, a controlled
study of cardiac function, assessed by echocardiography of
387
13 adults with GH deficiency compared with controls, revealed no cardiovascular dysfunction in the patients (88).
The long term effects of GH replacement on cardiac function are unknown; however, patients with acromegaly have
an increased prevalence of left ventricular hypertrophy, hypertension, cardiac failure, and cardiovascular death compared with the healthy population (89 –93). GH replacement
should be aimed at restoring somatic deficiency, including
cardiac size and function, and supraphysiological replacement should be avoided.
In summary, patients with long standing GH deficiency
have reduced life expectancy largely related to increased
mortality from cardiovascular disease. GH deficiency results
in smaller left ventricular size and impaired ventricular function. These changes can be reversed by GH replacement and
sustained benefit is seen up to 3 yr after commencement of
GH therapy.
VII. Metabolism
A. Energy expenditure
Whole body energy expenditure is largely determined by
lean body metabolic activity (94). Resting energy expenditure (REE) has been shown to be increased in acromegaly (95,
96). Recent studies (97, 98) have shown that REE in adults
with GH deficiency is lower than predicted values corrected
for age, height, and weight. Another study of seven adults
with GH deficiency had similar findings, but the difference
in REE compared with controls failed to reach statistical
significance (16). Expressing REE per LBM in these studies
produced conflicting results, with an increase in REE observed in the first, a decreased REE in the second, and a value
similar to that in healthy subjects in the third (16, 97, 98)
study. Methodological differences in the measurement of
LBM may be responsible for these discrepancies.
GH replacement in GH deficiency results in rapid and
large increases in REE (6, 16). Restoration of LBM accounts
for much of the increase observed in REE, but when changes
in REE are expressed per LBM, these rises are still significant,
indicating that direct increases in cellular metabolism are
responsible for some of the increased REE (6). GH treatment
of the GH-deficient adult results in an increase in circulating
T3 levels in both patients receiving T4 replacement and those
with normal thyroid function (6, 12, 99, 100), indicating that
GH is a physiological regulator of thyroid function in general
and of peripheral conversion of T4 in particular. This alteration may contribute to the calorigenic effect of GH. In addition, GH replacement has been shown to increase fat oxidation (101–103) and protein synthesis (15, 104, 105). These
processes are energy dependent and result in an increase in
energy expenditure.
B. Protein metabolism
Although there have been many studies of the effects of
GH on body composition in the GH-deficient adult, there
have been comparatively few studies of the direct effects of
GH replacement on protein metabolism in these patients.
These studies are reviewed below.
Binnerts et al. (15) performed a 6-month open study of the
effects of GH replacement (0.5 IU/kgzday; 25 mg/kgzday) in
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CARROLL ET AL.
eight adults with GH deficiency using [15N]glycine as a
tracer. Protein synthesis was increased at 1 month, with no
alteration in protein degradation. This effect was unsustained and was no longer evident after 3, 6, or 9 months of
GH therapy. Importantly, throughout the study when rates
of protein metabolism were expressed in terms of LBM, no
significant differences were detectable throughout the entire
study duration.
In a study of 16 adults with GH deficiency compared with
20 matched controls, Beshyah et al. (104) used l-[113
C]leucine to study protein metabolism. The patients had
decreased leucine flux, oxidation, and protein synthesis.
Seven of these patients underwent an identical study after 6
months of GH therapy (0.18 – 0.35 IU/kgzweek; 9 –17.5 mg/
kgzday), which demonstrated a nonsignificant increase in
protein flux, oxidation, and synthesis.
A randomized, double blind, placebo-controlled trial of
the effect of GH replacement (0.25 IU/kgzweek; 12.5 mg/
kgzday) on protein metabolism involving 18 GH-deficient
adults was performed using l-[1-13C]leucine (105). In this
study, protein synthesis was significantly increased after 2
months (24%), with no alteration in protein degradation.
The major alterations in body composition occur within 1
month of commencement of GH therapy (6, 7), and it is likely
that any significant alteration in protein metabolism would
occur over this period. This may account for the results of the
studies of protein metabolism, which have demonstrated an
increase in protein synthesis up to 2 months (105) after commencement of GH, but little alteration above baseline after 6
months of therapy (15).
In summary, studies of protein metabolism in adults with
GH deficiency have demonstrated reduced protein flux and
synthesis. GH replacement increases protein synthesis for
the first few months, with a return to baseline rates after 6
months, most likely as a result of achieving a new baseline
rate of metabolism.
C. Carbohydrate metabolism
Adults with GH deficiency have altered body composition
and tend to be obese, with an increase in central adiposity (7,
14). A study of 24 adults with GH deficiency demonstrated
fasting insulin levels above the normal reference range and
a significant positive correlation between fasting plasma insulin and both fat mass and waist girth (6). Adults with GH
deficiency are thus likely to be insulin resistant. This has been
confirmed in a hyperinsulinemic euglycemic clamp study of
9 adults with CO GH deficiency (106). Similarly, using
a hyperinsulinemic euglycemic clamp (40 mU/m2zmin),
Johansson et al. (109) demonstrated a decreased glucose infusion requirement in 15 adults with GH deficiency compared with that in matched controls, indicating reduced insulin sensitivity. Similar plasma insulin levels were seen
between the 2 groups (in the normal range).
In a double blind, placebo-controlled, cross-over study,
Fowelin et al. (107) assessed the effects of 6 months of GH
replacement (0.25 IU/kgzweek; 12.5 mg/kgzday) on glucose
metabolism in nine adults with GH deficiency. Using d-[33
H]glucose tracer and a hyperinsulinemic euglycemic clamp,
they investigated basal glucose and insulin-stimulated glu-
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cose metabolism after 6 weeks and 6 months of GH treatment. After 6 weeks of GH therapy, fasting glucose levels and
plasma insulin concentrations were elevated, but both had
returned to baseline at 26 weeks. The amount of glucose
required for euglycemia during the insulin clamp was significantly lower after 6 weeks of therapy, but there was no
difference above baseline at 26 weeks. These changes were
interpreted as a short term reduction of insulin-stimulated
glucose utilization, mediated by GH, with reversal of these
changes with time, perhaps as a result of altered body
composition.
Using an iv glucose tolerance test, O’Neal et al. (108) performed an uncontrolled study of the effects of GH replacement (0.25 IU/kgzweek; 12.5 mg/kgzday) on glucose metabolism in 10 GH-deficient adults. Employing Bergman’s
minimal model, these studies demonstrated increased fasting glucose, insulin, and C peptide as well as an increase in
both the first and second phases of insulin secretion after 1
week of GH therapy. Insulin-mediated glucose disposal and
glucose decay were decreased, but the fractional clearance
rate of insulin was unchanged. After 3 months of GH treatment, the fasting plasma insulin and C peptide concentrations remained elevated, but all other variables had returned
to baseline values.
Salomon et al. (97) assessed fasting glucose metabolism in
24 GH-deficient adults using d-[3-3H]glucose and indirect
calorimetry. In these studies, glucose turnover was within
the normal range for healthy adults (expressed per LBM).
During the course of the study, glucose turnover correlated
positively with fat oxidation, and a reduction occurred in
glucose oxidation. These changes are consistent with those
observed in normal adults during a prolonged fast and suggest that adults with GH deficiency have reduced stores of
glycogen.
Hew et al. (110) assessed glucose metabolism in 14 adults
with GH deficiency and 12 matched controls using a hyperinsulinemic euglycemic clamp, with measurement of glycogen synthetic rate by muscle biopsy. Both groups had similar
basal rates of glucose utilization, but a reduction (64%) in
insulin-stimulated glucose utilization occurred in the GHdeficient adults compared with that in the control subjects.
In addition, the insulin sensitivity index of glucose disposal
and glycogen synthesis were reduced in the patients. The
insulin-stimulated fractional velocity was decreased by 50%
compared with that in controls. These data confirm that
patients with GH deficiency have insulin resistance, with
inhibition of the glycogen synthase pathway.
In summary, GH-deficient adults have hyperinsulinemia,
indicating insulin resistance. These features are associated
with the central obesity and increased intraabdominal adiposity that are characteristic of GH deficiency. Most of the
hyperinsulinemic euglycemic clamp studies have confirmed
this insulin resistance. In addition, there is evidence that
adults with GH deficiency have reduced hepatic glycogen
stores. GH replacement has been demonstrated to further
increase insulin resistance over a period of 1– 6 weeks of
therapy, but although hyperinsulinemia persists, carbohydrate metabolism returns to baseline after 3 months of GH
treatment.
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D. Lipid and lipoprotein metabolism
389
iii. Lipoprotein(a) [Lp(a)]
The only exception to the trend of normalization of cardiovascular risk factors after GH treatment is Lp(a), a proposed independent risk factor for the development of atherosclerosis and myocardial infarction (120, 121). Lp(a) levels
rose in five of six studies (26, 113, 116, 118, 122) and did not
change in only one study (114). The importance of this observation is not yet clear.
1. Plasma lipid and lipoprotein profile in adult GH deficiency. The
findings from studies comparing plasma lipids and lipoproteins in GH-deficient adults with those in age-matched
healthy controls are summarized in Table 6. Elevated concentrations of total cholesterol (TC), low density lipoprotein
cholesterol (LDL-C), and apolipoprotein B (ApoB) have been
observed in a substantial proportion of patients compared
with those in age- and sex-matched controls or with the
predicted range (33, 111, 112). HDL-C levels tend to be low
(33, 76, 112) and TG levels high compared with those in
healthy controls (76, 79, 112). Thus, GH deficiency appears to
be associated with a lipid profile known to be related to
premature atherosclerosis and cardiovascular disease.
3. Proposed mechanism of action of GH on lipid and lipoprotein
metabolism. GH directly stimulates the liberation of free fatty
acids within the first weeks of treatment (102, 123). Free fatty
acids can be oxidized in the peripheral tissues or taken up by
the liver and reesterified into triglycerides (124).
In hypophysectomized rats, GH appears to stimulate very
low density lipoprotein (VLDL) secretion in parallel with a
stimulation of the editing of ApoB48, leading to a increased
clearance of VLDL because of the shorter half-life of VLDLApoB48 compared with that of VLDL-ApoB100 (125). Consequently, a decreasing fraction of VLDL is converted into
LDL, resulting in a decreased synthetic rate of LDL.
LDL-C clearance is regulated by the availability of hepatic
LDL receptors. Studies in rats and humans (126) have shown
that the administration of GH leads to up-regulation of hepatic LDL receptor and therefore to increased clearance of
LDL-C (124). A stable isotope study in eight hyperlipidemic
GH-deficient patients demonstrated an increased rate of
VLDL-ApoB secretion and a decreased VLDL MCR compared with those of age-, sex-, and body mass index-matched
controls (127).
These studies confirm that GH is involved in the regulation of hepatic lipoprotein metabolism and may therefore
influence the lipid and lipoprotein profile seen in patients
with AO GH deficiency. It is too soon to understand fully the
complex action of GH on lipid metabolism; however, the
major effects of GH replacement include a reduction in
LDL-C and an increase in the circulating concentration of
Lp(a). Long term observation will be required to determine
whether GH replacement results in a regression of premature
atherosclerosis and a reduction in cardiovascular morbidity
and mortality of adults with GH deficiency.
2. Effect of GH replacement on the plasma lipid and lipoprotein
profile in adults with GH deficiency
i. Double blind, placebo-controlled trials
The results of seven studies are reported (Table 7) (6, 14,
33, 112–116). The duration of GH therapy in these studies was
at least 2 months, and in most cases it was 6 months. The dose
of GH in these trials was 0.25 IU/kgzweek (12.5 mg/kgzday),
with the exception of the first study (6), in which the patients
were treated with 0.5 IU/kgzweek (25 mg/kgzday).
GH replacement resulted in a decrease in the TC concentration in six of the seven studies (6, 33, 114 –116) and was
accompanied by significant decreases in LDL-C and ApoB
(112, 114). In addition, GH therapy was associated with an
increase in HDL-C, which reached significance in two of
these trials (33, 113). Similar findings were reported from a
small open study (15). The plasma concentrations of TG and
ApoA did not change significantly after GH treatment (6, 14,
112–116); however, there was a tendency for reduced TG
with GH treatment in those patients with elevated TG concentrations at baseline (113). In patients with CO GH deficiency, TC did not significantly change, although there was
a tendency for decreased levels after 6 months of GH treatment (33).
ii. Open trials lasting more than 12 months
There are four open trials lasting more than a year (26, 33,
117–119). The results of these studies have shown that the
favorable effects of GH replacement on the plasma lipid and
lipoprotein profile are sustained up to 4 yr after commencement of GH. It appears that the observed decrease in TC
concentration is followed by an increase in HDL-C, a finding
that occurs similarly in the GH deficiency of both AO and CO
(24, 26, 33).
VIII. Skin
Skin thickness and total skin collagen are reduced in hypopituitary adults despite conventional replacement therapy, and the converse is true in acromegaly (128). An increase
in skin thickness was demonstrated after GH treatment in
TABLE 6. Lipid and lipoprotein profile in adults with GH deficiency compared with controls
Yr
n
TC
TG
HDL-C
LDL-C
ApoB
Note
Cuneo (112)
Rosen (2)
Author
1993
1993
24 (MO)
104 (MO)
a
N
a
a
s
s
a
a
Johansson (79)
de Boer (111)
Attanasio (33)
1994
1994
1997
N
a
a
a
a
N
N
s (CO)
s (AO)
a
a
Wt-matched control group
Population-based normal controls
(WHO MONICA study)
Wt-matched control group
Age- and sex-matched control group
Compared with normal range
20
64
74
99
(AO)
(CO)
(CO)
(AO)
n, Number of patients; TC, total cholesterol; TG, triglyceride; HDL-C, HDL cholesterol; LDL-C, LDL cholesterol; ApoB, apolipoprotein B;
CO, childhood-onset GH deficiency; AO, adult-onset GH deficiency; MO, mixed onset GH deficiency; a/s, statistically significant increase/
decrease vs. controls; N, no significant change.
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TABLE 7. The effect of GH replacement therapy on the lipid and lipoprotein profile in adult GH deficiency
Duration
(months)
Author
Yr
n
Design
Salomon (6)
Cuneo (112)
Binnerts (15)
Whitehead (14)
Eden (113)
Russell-Jones (114)
Beshyah (115)
1989
1993
1992
1992
1993
1994
1995
Weaver (116)
1995
Johansson (117)
Johansson (26)
Al-Shoumer (118)
Garry (119)
Attanasio (33)
1995
1995
1996
1996
1997
24 (MO)
24 (MO)
8 (AO)
14 (MO)
9 (AO)
18 (MO)
20 (MO)
20 (MO)
22 (MO)
22 (MO)
44 (AO)
34 (AO)
13 (?)
21 (AO)
74 (CO)
99 (AO)
DBPC
DBPC
Open
DBPC/CO
DBPC/CO
DBPC
DBPC
Open
DBPC
Open
Open
Open
Open
Open
DBPC
Open
TC
6
s
6
s
6
s
6
N
6
N
2
s
6
N
12
s
6
s
12
N
12
s
24
N
48
s
36
N
6 (CO) N, (AO) s
12/18 (CO) N/N, (AO)
N/N
TG
HDL-C
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
a
N
a
N
N
a
LDL-C
s
N
N
s
N
s
a
s
a
N
s
a
(CO) a, (AO) a
(CO) N, (AO) s
(CO) a/a, (AO) a/a
ApoB ApoA Lp(a)
s
N
N
s
N
N
s
s
s
N
N
N
N
N
N
N
a
N
N
a
a
a
n, Number of patients; TC, total cholesterol; TG, triglyceride; HDL-C, HDL cholesterol; LDL-C, LDL cholesterol; ApoB, apolipoprotein B100;
ApoA, apolipoprotein A; Lp(a), lipoprotein (a); CO, childhood-onset GH deficiency; AO, adult-onset GH deficiency; MO, mixed onset GH
deficiency; a/s/N, increased, decreased, and unchanged concentrations, respectively, in patients with AO GH deficiency after GH replacement
therapy.
normal elderly males selected on the basis of low IGF-I levels
(129). Hypopituitary adults are usually described as having
dry and thin skin, whereas excessive sweating is a typical
feature of acromegaly, and eccrine sweat glands have been
shown to possess GH receptors (130). The sweat secretion
rate measured in response to pilocarpine iontophoresis was
significantly lower in GH-deficient adults than in age- and
sex-matched control subjects, and during GH treatment, it
increased sufficiently to be perceived by the patients (131).
More recently, GH-deficient adults have been shown to have
an impaired ability to dissipate heat by sweating after heat
stress or exercise (132), and this may be an important contributory factor to their reduced exercise capacity.
IX. Immune Function
Human peripheral blood T cells, B cells, natural killer (NK)
cells, and monocytes express IGF-I receptors. Animal studies
suggest a role for IGF-I, and therefore GH, in the modulation
of both cell-mediated and humoral immunity. Administration of either GH of IGF-I can reverse the characteristic immunodeficiency of Snell dwarf mice (133, 134).
Human adults with GH deficiency do not usually have
compromised immunocompetence. Evidence suggests that
GH therapy does not have significant effects on either T or
B cell function (135–137). Hypophysectomized mice display
decreased NK cell activity (138), and an improvement in NK
cell function has been observed with GH replacement (139).
Whether similar effects occur in humans is not known.
X. Psychological Well-Being and Quality of Life (QoL)
The psychological well-being and QoL of GH-deficient
patients and the effects of GH replacement have received
considerable attention in recent years. In most studies, selfperceived well-being and QoL have been assessed using
validated questionnaires, and comparisons have been made
with controls of matched age, sex, and socio-economic status.
Decreased psychological well-being has been reported in
hypopituitary adults despite replacement of all hormone
deficiencies with the exception of GH (140). Using the Nottingham Health Profile (NHP), Rosen et al. (141) compared
psychological well-being in 86 adults with GH deficiency
with that in 86 age-matched controls. In this study the GHdeficient patients reported less energy, greater emotional
lability, more difficulties with sexual relationships, and a
greater sense of social isolation than the control subjects.
Stabler et al. (140) evaluated psychosocial adjustment in
adults with GH deficiency and in age-, sex-, socio-economic
statys-, and height-matched controls. Those with multiple
pituitary hormone deficiencies showed less openness and
less assertiveness compared with controls.
In a double blind, placebo-controlled study, McGauley et
al. (142) were the first to demonstrate that GH replacement
(0.5 IU/kgzweek; 12.5 mg/kgzday) was associated with an
improvement in mood and energy levels in GH-deficient
adults. In this study three instruments that assess general
health and well-being, the NHP, the Psychological and General Well-Being Schedule (PGWB), and the General Health
Questionnaire, all showed significant improvements in subjective well-being and QoL after 6 months of GH replacement. This study was performed without knowledge or expectation of the psychological effects of GH therapy, issues
that may be relevant in the interpretation of subsequent
studies.
Whitehead et al. (14) examined the effects of GH replacement (0.25 IU/kgzweek; 12.5 mg/kgzday) on well-being of 14
adults with GH deficiency in a 6-month, double blind, placebo-controlled, cross-over trial using the NHP and the
PGWB. No significant changes in psychological well-being
were observed, but many patients failed to demonstrate a
significant increase in IGF-I, indicating that noncompliance
with GH may have accounted for these findings. Using 2
QoL-rating scales [Comprehensive Psychological Rating
Scale (CPRS) and Symptom Checklist-90], Bengtsson et al.
(12) examined the effects of 6-month GH replacement (0.25
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IU/kgzweek; 12.5 mg/kgzday) in 26 adults with GH deficiency in a double-blind, placebo-controlled, cross-over
study. GH treatment was associated with a significant improvement in the CPRS, but not in the Symptom Checklist90. Using the CPRS and General Health Questionnaire-90,
Beshyah et al. (29) examined the effects of GH replacement
(0.18 – 0.35 IU/kgzweek; 9 –17.5 mg/kgzday) on 40 adults in a
randomized controlled trial. The initial 6 months were randomized, but thereafter, patients continuing on GH replacement were followed for 18 months. Those initially randomized to placebo reported greater morbidity at baseline, and
placebo was associated with a significant improvement in
CPRS compared with GH after 6 months of therapy. Compared to the baseline score, patients receiving GH reported
an improved CPRS score after 6 and 12, but not 18, months
of therapy.
Burman et al. (143) examined psychological capacity and
sense of well-being using the Hopkins Symptoms Check List
(HSCL), the NHP, and the PGWB in 36 adults with GH
deficiency and 36 matched controls. Those with GH deficiency reported a lower QoL, as assessed by the HSCL and
NHP. The severity of their distress correlated positively with
the duration of GH deficiency. Twenty-one of the patients
entered a cross-over, double blind, placebo-controlled study
of the effects of GH replacement (0.25 IU/kgzweek; 12.5 mg/
kgzday) on these measures. The HSCL score improved during the placebo phase, but fell further during active treatment. Active treatment was associated with improvement in
the energy and emotional subsections of the NHP. In addition, spouses of the patients reported improved mood and
behavior in the subjects during the GH treatment phase.
An uncontrolled study with a small sample size suggested
that GH replacement may result in improved memory in
adults with GH deficiency (144). The direct mechanism behind alterations in perceived QoL remain unknown. Recently, GH treatment of GH-deficient adults has been shown
to alter levels of vasoactive intestinal polypeptide and the
dopamine metabolite, homovanillic acid, as well as elevate
b-endorphin levels in cerebrospinal fluid, but whether these
changes are responsible for improvements in mood and wellbeing is not yet known (145). GH, IGF-I, and the IGF-binding
proteins may have direct effects on the nervous system. In
addition, abnormal sleep patterns have been described in
GH-deficient adults, with a restoration to normal patterns
after GH replacement (146, 147).
The interpretation of more recent studies of the psychological effects of GH replacement must be made with caution,
as maintaining a true double blind protocol is difficult. Patients and physicians may associate common side-effects,
such as fluid retention and arthralgia, with active treatment,
resulting in biased reporting. In addition, GH-deficient
adults who wish to enter a trial of GH therapy may be the
patients with the most severe psychological distress, and any
interpretation of studies of the psychological effects of GH
replacement must allow for this observation (148).
In summary, adults with GH deficiency report reduced
psychological well-being and QoL compared with matched
healthy controls. Trials of the effects of GH replacement have
demonstrated improvements in psychological well-being
and QoL.
391
XI. Reported Adverse Effects of GH Replacement
As recombinant GH has exact sequence homology with
natural human GH, side-effects result from excess replacement alone. The GH replacement dose used in early trials (12,
6, 7, 14, 15, 67) was based on those used for the treatment of
GH-deficient children (;0.5 IU/kgzweek; 25 mg/kgzday). In
these trials, clinically relevant adverse effects resulted in a
dose reduction in up to 40% of patients. In addition, circulating IGF-I levels were excessively high in a similar number
of patients, suggesting that this replacement dose was supraphysiological. Consequently, more recent studies (16, 21,
27, 39, 54) have employed smaller doses of GH.
Evidence suggests that those patients most at risk from
adverse effects of GH replacement are older and more obese,
with a greater GH response on provocative testing, and the
largest IGF-I rise after GH treatment (149). The most common
side-effects after GH treatment in GH-deficient adults are
those arising from sodium and water retention. Weight gain,
dependent edema, a sensation of tightness in the hands, or
symptoms of carpal tunnel compression frequently occur
within days or weeks. A study of GH replacement in 233
hypopituitary adults, with GH doses ranging from 0.08 – 0.3
IU/kgzweek (4 –15 mg/kgzday) resulted in fluid retention
(37.4%), arthralgia (19.1%), and muscle pains (15.7%) in the
first 6 months of treatment (150). These symptoms resolve
rapidly with dose reduction or occasionally disappear over
several weeks without any action. Blood pressure has not
changed significantly after up to 3 yr of GH treatment (85).
Arthralgias involving small or large joints occur in some
patients during GH treatment, but there is usually no evidence of effusion or inflammation, and x-rays have shown no
abnormality (6). These changes also settle with dose reduction and are possibly due to swelling of articular cartilage,
although the precise mechanism remains unknown. Myopathy and arthralgia commonly occur in acromegaly, and it is
likely that these symptoms arise from GH excess (151–154).
Little information is available regarding the effect of GH
treatment on tumor development and recurrence in adults
with GH deficiency. Data from long term studies in children
with both solid tumors and hematological malignancies suggest that there is no increased risk of recurrence associated
with GH therapy (155–158).
GH therapy is recognized to result in hyperinsulinemia
(159), which may increase the risk of cardiovascular complications (160), as can elevated serum Lp(a) (121). GH-induced hypertension (6) and atrial fibrillation (12) have been
reported, but are rare occurrences. There have been isolated
reports of cerebral side-effects in the form of encephalocele
(6) and headache with tinnitus (12). Benign intracranial hypertension (BIH) has also been reported in association with
GH therapy (161). The majority of affected patients are children, and the BIH has improved with cessation of therapy.
Papilloedema was present in the majority of cases. IGF-I has
also been reported to cause BIH and papilloedema (161).
Cessation of IGF-I therapy has resulted in regression in all
reported cases (161). Gynecomastia has been reported as a
rare occurrence in elderly men (162).
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XII. Concluding Remarks
Acknowledgments
The importance of GH throughout adult life is now unequivocally accepted. GH deficiency is recognized to result
in alterations in body composition, physical performance,
psychological well-being, and substrate metabolism. Many
of these alterations can be improved or corrected with GH
replacement. It is likely that GH replacement will in the near
future become as routine as steroid, thyroid hormone, and
sex hormone replacement in management of the hypopituitary adult. The major restriction to the widespread use of GH
is cost. It is expected that once the pharmaceutical industry
has recovered its developmental expenditure, the cost of GH
will decrease.
The prospect of GH replacement becoming routine, however, does raise a number of issues. The most fundamental
of these relates to the selection criteria of patients who may
benefit from GH therapy. Most of the studies to date have
focused on those with absent or profoundly reduced GH
secretion. The effect of GH replacement on those with partial
GH deficiency has not been addressed. The selection of patients is further complicated by the marked age-associated
decline in GH secretion (163, 164). Many elderly patients
would meet diagnostic criteria for GH deficiency, and
whether such patients would benefit from GH therapy is
unknown. In addition, GH secretion is higher in females than
in aged-matched males (165), and increasing BMI is associated with a decline in GH secretion (165). Current practice
focuses on those patients in whom GH deficiency is present
without doubt, and in whom GH replacement has been
shown to be of benefit.
The optimal dose of GH replacement for the GH-deficient
adult has been the subject of discussion. Early studies employed GH doses that produced IGF-I concentrations in excess of the age-matched normal range and unacceptably high
rates of adverse effects (6, 7, 12, 14, 15, 67). As a result, lower
doses have been used in more recent studies, which have
been better tolerated (16, 21, 27, 39, 54). The choice of replacement therapy has been further complicated by a recent
study that demonstrated a marked individual variability in
biochemical and body composition responses to GH replacement (165). In this study, men had a greater body composition response to GH therapy than women, and younger
patients with low levels of GH-binding protein had the greatest responses.
In the majority of studies, the effect of GH replacement has
been rigorously assessed over 6- or 12-month periods. The
longer term effects have not been fully addressed, and it
remains to be seen whether GH treatment will reduce the
incidence of cardiovascular and bone disease over a period
of years. There is a need for prospective clinical studies to
further guide the duration of GH replacement.
The prospect of life-long GH replacement for many GHdeficient adults means that resources and facilities for long
term monitoring must be present. Such monitoring will provide further information regarding the long term issues of
GH treatment, such as tumor development, but also determine whether GH replacement is associated with an increase
in life expectancy for the GH-deficient adult.
This review details the available evidence relating to the consequences of GH deficiency and the effects of GH replacement in the
GH-deficient adult. Particular emphasis is made on controlled studies
that have been fully reported after peer review. To provide the most
current evidence, references are included from abstracts presented at the
1996 meeting of the GRS (London, UK). These are highlighted by an
asterisk.
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